1. Field of the Invention
This invention is in the field of prevention and treatment of liver cirrhosis.
2. Description of the Prior Art
Liver fibrosis, regardless of its cause, is characterized by marked accumulation of extracellular matrix in the perisinusoidal space (Rojkind M, Giambrone M. A., Biempica L. Collagen types in normal and cirrhotic liver. Gastroenterology 1979; 76: 710-719; Murata K, Kudo M, Onuma R, Motoyama T. Changes of collagen types at various stages of human liver cirrhosis. Hepato-Gastroenterology 1984; 31: 158-161). Many efforts have been made to identify the cellular sources of extracellular matrix proteins in intact liver. Some observations have suggested that parenchymal liver cells play a central role in the production of interstitial collagen (Martinez-Hernandez A. The hepatic extracellular matrix. I. Electron immunohistochemical studies in normal rat liver. Lab Invest 1984; 51: 57-74; Sakakibara K, Igarashi S, Hatahara T. Localization of type III procollagen aminopeptide antigenicity in hepatocytes from cirrhotic human liver. Virchows Arch [A] 1985; 408: 219-228; Chojkier M, Lyche K. D., Filip M. Increased production of collagen in vivo by hepatocytes and nonparenchymal cells in rats with carbon tetrachloride-induced hepatic fibrosis. Hepatology 1988; 8: 808-814). Other experiments, however, have led to the conclusion that hepatic extracellular matrix production is largely a function of mesenchymal liver cells (Milani S, Herbst H, Schuppan D, Hahn E. G., Stein H. In situ hybridization for procollagen types I, III and IV mRNA in normal and fibrotic rat liver: evidence for predominant expression in nonparenchymal liver cells. Hepatology 1989; 10: 84-92; Friedman S. L., Roll F. J., Boyles J, Bissell D. M. Hepatic lipocytes: the principal collagen-producing cells of normal rat liver. Proc Natl Acad Sci USA 1985; 82: 8681-8685). Lipocytes (fat-storing or Ito cells), the principal cells in the Disse space of the liver, were found to synthesize and release different types of collagen (Clement B, Grimaud J. A., Campion J. P., Deugnier Y, Guillouzo A. Cell types involved in collagen and fibronectin production in normal and fibrotic human liver. Hepatology 1986; 6: 225-234), and they are considered to play an important role in the development of alcohol-induced liver fibrosis (Minato Y, Hashamura Y, Takeuchi H. The role of fat-storing cells in Disse space fibrogenesis in alcoholic liver disease. Hepatology 1983; 3: 559-566). Previous studies have reported that acetaldehyde stimulates collagen production in vitro (Moshage H, Casini A, Lieber C. S. Acetaldehyde selectively stimulates collagen production in cultured rat liver fat-storing cells but not in hepatocytes. Hepatology 1990; 12: 511-518) and increases procollagen type I gene transcription in cultured lipocytes (Casini A, Cunningham M, Rojkind M, Lieber C. S. Acetaldehyde increases procollagen type I and fibronectin gene transcription in cultured rat fat-storing cells through a protein synthesis-dependent mechanism. Hepatology 1991; 13: 758-765). In vivo, the progression liver fibrosis was accompanied by the transformation of lipocytes to transitional cells in fatty livers with perivenular fibrosis or cirrhosis, with a significantly higher collagen score in the Disse space surrounding transitional cells compared with that surrounding lipocytes (Mak K. M., Leo M. A., Lieber CS. Alcoholic liver injury in baboons: transformation of lipocytes to transitional cells. Gastroenterology 1984; 87: 188-200; Mak K. M., Lieber C. S. Lipocytes and transitional cells in alcoholic liver disease: a morphometric study. Hepatology 1988; 8: 1027-1033). In addition to collagen production, collagen breakdown determines the degree of collagen accumulation. Collagenase activity is generally increased during the early stage of liver injury (Maruyama K, Feinman L, Okazaki I, Lieber C. S. Direct measurement of neutral collagenase activity in homogenates from baboon and human liver. Biochim Biophy Acta 1981; 658: 124-131). Previous studies revealed that fibrosis coincides with the state at which collagen breakdown slackens and stops keeping pace with increased production (Maruyama K, Feinman L, Fainsilber Z, Nakano M, Okazaki I, Lieber CS. Mammalian collagenase increases in early alcoholic liver diseases and decreases with cirrhosis. Life Science 1982; 30: 1379-1384). Therefore these findings suggested that studies of the production and regulation of collagenase activity during liver injury may be relevant to the elucidation of the pathogenesis of liver fibrosis.
Membrane alterations are a striking component of alcohol-induced liver injury (Yamada S, Mak K. M., Lieber C. S. Chronic ethanol consumption alters rat liver plasma membranes and potentiates release of alkaline phosphatase. Gastroenterology 1985; 88: 1799-1806). Phosphatidylcholine may directly influence membrane structures and provide a basis for some of the beneficial effects of essential phospholipids in the treatment of liver diseases (Kuntz E. Pilotstudie mit Polyenylphosphatidylcholin bei schwerer Leberinsuffizien. Med Welt 1989; 40: 1327-1329). Recently, it was reported that polyunsaturated lecithin (PUL) extracted from soybeans can prevent fibrogenesis in alcohol-fed baboons. None of the animals fed PUL progressed beyond the stage of perivenular fibrosis. Furthermore, when three of the ethanol-PUL-treated animals were no longer given PUL but continued to ingest the same amount of the ethanol-containing diet, they rapidly progressed to more severe stages of fibrosis, including cirrhosis, illustrating again the protective effect of PUL (Lieber C. S., DeCarli L. M., Mak K. M., Kim C. I., Leo M. A. Attenuation of alcohol-induced hepatic fibrosis by polyunsaturated lecithin. Hepatology 1990; 12: 1390-1398).